This retrospective study was approved by the Institutional Review Board of Samsung Medical Center (2021-06-086), and the requirement for informed consent was waived.

This study used a longitudinal hospital registry from a single tertiary referral hospital. Patients who underwent either PRFA or LRFA as primary HCC treatment between January 2013 and December 2018 were included. In total, 1,816 patients were treated with PRFA. Among them, 1,565 were excluded for the following reasons: HCC treatment history (n=1,164), loss to follow-up after 1 month (n=35), other concurrent malignancy (n=160), multiple HCCs (n=32), HCC size of >3 cm (n=22), and tumor size of <1 cm (n=152). Tumor size was measured in the sequences that showed the best conspicuity of the tumor in dynamic enhanced liver magnetic resonance imaging (MRI). If the tumor had low signal intensity on the hepatobiliary phase, that sequence was preferred, and the longest diameter of the tumor was measured on either axial or coronal images. Two radiologists reviewed the computed tomography (CT) and MRI scans obtained before RFA and reached a consensus on the tumor location (subphrenic or non-subphrenic). Finally, 221 patients were further excluded because the HCC had a non-subphrenic location. Subphrenic tumors were defined as those abutting the diaphragm. Tumor size was defined based on the longest diameter on CT or MRI. Finally, 30 patients treated with PRFA for subphrenic HCC were included.

LRFA was performed in 124 patients. Among them, 84 were excluded for the following reasons: HCC treatment history (n=74), other concurrent malignancy (n=2), multiple HCCs (n=6), HCC size of >3 cm (n=1), and advanced HCC with bile duct invasion (n=1). The pretreatment images were also reviewed, and 17 patients were excluded due to tumors with a non-subphrenic location. Finally, 23 patients treated with LRFA for subphrenic HCC were included. Fig. 1 shows the flow diagram of patient selection. The HCC diagnosis was based on current clinical guidelines [15].

Planning US was performed by interventional radiologists to assess whether PRFA was feasible using fusion imaging (Volume navigation, LOGIQ E9, GE Healthcare, Chicago, IL, USA) of B-mode US and pretreatment CT/MRI, obtained within 1 month prior to the procedure [16]. Fusion imaging was routinely used for treatment planning regardless of lesion conspicuity. When PRFA was considered feasible, it was attempted by the same radiologists, who had more than 3 years of experience in RFA for hepatic tumors.

Radiofrequency electrodes were inserted under fusion imaging guidance; direct tumor puncture was avoided when the tumor was located in the anterior liver dome to prevent peritoneal seeding. Based on the tumor size and location, the choice was made to use an active tip length-adjustable internally cooled tip (Proteus RF Electrode, STARmed, Goyang, Korea), an internally cooled wet tip, a kind of perfusion electrode with various active tip lengths (Jet-tip, RF Medical, Seoul, Korea), or clustered separable electrodes with an internally cooled tip with different active tip length (Octopus Electrode, STARmed). To achieve a sufficient ablative margin, peripheral tumor-puncturing or no-touch RFA was preferred when using multiple electrodes or overlapping ablation when using a single electrode. The radiologist ensured that the index tumor was completely covered in the RFA zone based on US findings. The tract was cauterized during electrode removal.

LRFA was considered after planning US when the subphrenic HCC location appeared technically challenging for PRFA. When both PRFA and LRFA were feasible, the treatment method was determined by the radiologist. LRFA was performed by one of three radiologists while the patient was under general anesthesia. The surgeons introduced three or four trocars through the subcostal and subumbilical areas. The patients’ positions were manipulated to insert the radiofrequency electrode in the appropriate direction. A single electrode (Proteus RF Electrode, STARmed) or clustered separable electrodes (Octopus Electrode, STARmed) were used.

When the subphrenic tumors were broadly attached to the anterior liver capsule, they were well visualized on laparoscopy. The radiofrequency electrodes were inserted in parallel under laparoscopic guidance [14]. Whenever needed, overlapping ablations were performed for complete ablation with a sufficient ablative margin. Direct tumor puncture was avoided (video clip). Laparoscopic US (Aloka Inc., Tokyo, Japan) was also used for tumors focally attached to the liver capsule; thus, the tumors were not visualized on laparoscopy. The liver capsule was cauterized on top of the index tumor based on laparoscopic US findings for tumors not visible on laparoscopy, which facilitated accurate electrode placement. The electrode’s position in relation to the index tumor was assessed using laparoscopic US. The RFA zone was monitored to ensure that it was large enough to cover the entire tumor using laparoscopy and US. The tract was ablated during electrode removal.

Treatment response and complications were evaluated using contrast-enhanced CT on the day of the RFA. Treatment was considered technically successful if the RFA zone completely covered the index tumor on CT images [17]. A second RFA session was attempted within 24 hours after the first RFA session if technical success was not achieved. Technical efficacy was assessed on a 1-month follow-up CT or MRI scan. Major complications were defined as events that led to substantial morbidity and disability that increased the level of care, resulted in hospital admission, or substantially lengthened the hospital stay. All other complications were considered minor [17].

Follow-up contrast-enhanced CT/MRI was performed 1 month after initial treatment, every 3-4 months during the first 2 years, and every 4-6 months thereafter. Chest radiography, serum alpha-fetoprotein level measurements, and liver function tests were also performed. LTP was defined as the appearance of tumor foci at the edge of the ablation zone [17]. If recurrence, including LTP, intrahepatic distant recurrence (IDR), and extrahepatic metastasis (EM), occurred during follow-up, the multidisciplinary team decided on a suitable second-line treatment.

The length of the ablation zone was measured in 3-dimensions on immediate post-RFA CT. The maximum (Dmax) and minimum (Dmin) diameters of the ablation zone were measured from axial CT images and the longest vertical diameter (Dv) from coronal or sagittal images. The ablation volume was calculated using the formula for an ellipsoid lesion: ablation volume=π (Dmax×Dmin×Dv)/6 [18]. The ratios of the longest diameter and volume of ablation zone to those of the tumors were compared between the PRFA and LRFA groups.

Therapeutic outcomes, including LTP, IDR, EM, disease-free survival (DFS), and overall survival (OS), were compared between the two groups. DFS was defined as the time from the day of ablation to recurrence or death. OS was defined as the time from the initial treatment to death or the last follow-up date before April 30, 2021.

Demographic and clinical characteristics between the groups were compared using the t test, Wilcoxon rank-sum test, chi-square test, or Fisher exact test, as appropriate. Kaplan-Meier survival curves and the log-rank test were used to compare the cumulative LTP, IDR, EM, DFS, and OS rates. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Statistical significance was set at P<0.05.

The baseline characteristics of the patients, which are summarized in Table 1, were not significantly different between the PRFA and LRFA groups. Liver function, assessed using the Child-Pugh class or albumin-bilirubin grade, was not significantly different between the two groups. The serum levels of alpha-fetoprotein and protein induced by vitamin K absence-II were also not significantly different. More than 70% of the patients had hepatitis B virus-related liver disease, and the cause of liver disease was not significantly different between the two groups. The tumor size and location (Couinaud segment) were also not significantly different. The characteristics of the ablation technique are summarized in Table 2. They were not significantly different between the PRFA and LRFA groups.

In the PRFA group, a residual unablated tumor was noted in one patient (3.3%) on the immediate post-RFA CT images. The second RFA session was performed on the same day, which led to successful local tumor control. Technical efficacy was achieved in 30 patients (100%). Four of the 23 tumors in the LRFA group were indistinguishable on laparoscopy. These tumors were localized using laparoscopic US, and RFA was conducted. Both technical success and efficacy were achieved in all 23 patients (100%).

The median longest diameter of the ablation zone was 4.1 cm (range, 2.8 to 5.5 cm) in the PRFA group and 4.7 cm (range, 3.3 to 6.0 cm) in the LRFA group. The median volume of the ablation zone was 18.4 cm³ (range, 7.6 to 44.5 cm³) in the PRFA group and 28.7 cm³ (range, 8.4 to 43.5 cm³) in the LRFA group. The ratios of the longest diameter or the volume of the ablation zone to those of the tumors in both groups are summarized in Table 3. The ablation zone was significantly larger in the LRFA group than the PRFA group in comparison to the tumor.

Major complications were found in zero (0%) patients in the PRFA group and one (4.4%) patient in the LRFA group, respectively (P=0.434). In one patient, lung and liver abscesses were found 8 months after LRFA. The patient was treated with antibiotics without external drainage.

The duration of the hospital stay was significantly different between the two groups (PRFA: median, 3 days; range, 3 to 3 days vs. LRFA: median, 5 days; range, 4 to 6 days; P<0.001).